Innate modifiers of T cell behaviour during inflammatory disease

Abstract

Neutrophils are the most abundant leukocyte in mammals and represent one of the first lines of defence against invading microorganisms. In recent years, it has become clear that neutrophils are not only responsible for the killing of pathogens, but that they also play an important role in shaping adaptive immune responses. The aim of this project was to determine the role of the neutrophil-derived host defence peptide, cathelicidin, in the generation of Th17 responses during inflammation. Following inoculation with heat-killed Salmonella typhimurium, cathelicidin knockout mice cannot produce IL-17 and show increased IFNγ, whereas other cytokines are produced normally. Ex vivo, I show that cathelicidin is a novel Th17/Tc17 differentiation enhancing factor, which acts directly on both CD4+ and CD8+ T cells to increase their activation status, protect them from death and concentration-dependently upregulate IL-17 production. Gene expression analysis revealed that cathelicidin downregulates the expression of several Th1-related genes and upregulates the aryl hydrocarbon receptor (AHR), a known regulator of Th17 differentiation. The addition of an AHR antagonist to our in vitro cultures abolishes the boost to IL-17 production normally induced by cathelicidin. I provide further evidence that suggests lymph node neutrophils are the cellular source of cathelicidin, which are responsible for amplifying type-17 responses during inflammation. These data contribute to our understanding of how lymph node neutrophils influence developing adaptive immune responses with sophistication and specificity.